Clinical Significance. Biomaterials are widely used for devices that are implanted (e.g., catheters, defibrillators, stents, and sensors) and are being considered for tissue engineering applications to provide tissue restructuring after disease or injury. For all biomaterials, biocompatibility must involve not only an ability to integrate into the host, but also to function. Macrophage cells provide the chemical cues that act in synergy with the tissue that surrounds the implant to integrate it with the host. Despite many years of in vitro cell culture studies to assess the macrophage response to materials and in vivo histopathological experiments, a true theory of biocompatibility does not exist. Absolute confirmation of the in vivo signaling molecules involved has remained elusive due to lack of bioanalytical tools capable of addressing this complex chemical analysis problem. Achieving rapid progress in tissue bioengineering will require an in vivo understanding of the signaling chemicals involved at different temporal stages after biomaterial implantation. Experimental Approach. The proposed work has three specific aims. Aim 1 focuses on creating novel microdialysis sampling strategies for in vivo measurements of the foreign body response chemistry. Particular analyte targets include cytokines, eicosanoids, and matrix metalloproteinases. Aim 2 will use methods previously created in conjunction with Aim 1 to test the in vivo bioagent agent release to implanted biomaterials. Finally, Aim 3 will focus on understanding how different prophylactic approaches such as cytokine, drug, or growth factor release affects the underlying macrophage cellular signaling chemistry. Lay Public Health Statement. Implantation of effective devices or engineered tissue provides promise for improvement of quality of life under many circumstances. However, these devices often have incompatibility with the host and sometimes need to be removed. The frequency of the explantation process would be significantly reduced by a more quantitative approach to in vivo measurement of the responsible chemical signals associated with the foreign body response. Additional benefits may arise for the fields that require an intimate understanding and need to control a wound healing response such as plastic surgery.